Endometrial, ovarian, and breast cancers are among the top ten diagnosed and the most deadly for women in the United States. Despite advances in treatment, relapse and initial resistance to therapy continue to be problematic for these malignancies. Therefore, additional therapeutic strategies are urgently needed. The epithelial membrane protein-2 (EMP2) is a tetraspan membrane protein involved in cell adhesion, invasion, and signal transduction through the regulation of cell membrane composition. EMP2 is overexpressed on the surface of endometrial and ovarian cancers, and its expression is associated with a more aggressive phenotype and poor survival in patients with endometrial cancer. Importantly, new preliminary data show that EMP2 is overexpressed on a large number of breast cancer cells and its expression is independent of estrogen receptor, progesterone receptor, and HER2/neu status, making it an especially meaningful target for a generalized therapy. Additional preliminary data indicate that systemic administration of a human anti- EMP2 IgG1 reduces tumor load in human xenograft and syngeneic mouse breast cancer models. Although most antibody-based therapeutics used in the clinic are of the IgG class, IgE antibodies have intrinsic properties that make it attractive for anti-cancer therapy. IgE has a much higher affinity for its FcRs compared to IgG for its Fc?Rs. Additionally, these FcRs are expressed on key effector cells that are involved in the acute inflammatory response and antigen presentation. Moreover, the endogenous serum levels of IgE are very low in contrast to IgG. This decreases competition for FcR occupancy and eliminates the potential reduction in efficacy of the therapeutic antibody. Studies on the evaluation of IgE-based therapeutics for the treatment of cancer is part of the up-and-coming field of AllergoOncology. We now propose to open a new dimension in this field by developing an IgE that targets EMP2. Our central hypothesis is that a fully functional anti-EMP2 human IgE can be developed as a potential therapy of EMP2+ tumors, including endometrial, ovarian, and breast cancers. This novel antibody is expected to exhibit the intrinsic direct cytotoxicity of the anti-EMP2 IgG1 and to induce a distinct allergic reaction against the tumor consisting of a local Type I hypersensitivity reaction that leads to acute inflammation and eventually cancer cell destruction in the tumor microenvironment. It is also expected that the dead cells would be phagocytosed by antigen presenting cells and cancer antigens would be presented to the immune system resulting in a secondary cancer-targeted adaptive immune response. We propose three specific aims: Aim 1: To construct and express the fully human anti-EMP2 IgE; Aim 2: To study the functional properties of the anti-EMP2 IgE including antigen binding, FcR binding, and ability to induce degranulation of effector cells; Aim 3: To evaluate the direct in vitro anti-cancer effects of the anti-EMP2 IgE. Given the high expression of EMP2 on a number of malignancies, these studies will be important to establish the anti-EMP2 IgE as a potential therapeutic for cancers in women.